Mutation analysis of PAH gene in patients with PKU in western Iran and its association with polymorphisms: identification of four novel mutations

Abstract

Phenylketonuria (PKU) is an autosomal recessive disorder characterized by a mutation in the phenylalanine hydroxylase (PAH) gene. Untreated PKU can lead to mental retardation, seizures, and other serious medical problems. This study was designed to investigate the status of molecular defects in the PAH gene and their association with polymorphisms in Kurdish patients with PKU in the Kermanshah province, western Iran. The study was conducted on 27 unrelated patients with PKU over a 2-year period (from 2010 to 2012). All 13 exons plus exon-intron boundaries of the PAH gene were analyzed and we identified 15 different mutations, including two novel mutations, in 51 of the 54 mutant alleles (diagnostic efficiency of 94.4 %). IVS4 + 1G > C (c.441 + 1G > C) and IVS7 - 5 T > C (c.843 - 5 T > C) are novel mutations that have not been reported in the academic literature or the PAH locus database ( http://www.pahdb.mcgill.ca ); therefore, they may be specific to the Kurdish population. IVS2 + 5G > C and IVS9 + 5G > A were the two most prevalent mutations in our sample, with frequencies of 26 % and 17 %, respectively. The second most common mutations were p.R261X, IVS10 - 11G > A, p.K363 > Nfs and IVS7 - 5 T > C, with each showing a relative frequency of 7.4 %. All other detected mutations, including p.F55 > Lfs, p.R176X, p.R243Q, p.V230I, p.R243X, p.R261Q, IVS8 - 7A > G and p.E390G had frequencies of less than 4 %. The present study showed that there is a distinct difference in the characteristics of PAH mutations between the Kermanshah province and other parts of Iran, suggesting that Kermanshah may have a unique population distribution of PAH gene mutations. Iran lies on the route of major ancient movements of the Caucasian people toward the Mediterranean basin, and Kermanshah has previously been called the gateway to Asia. Most of the mutations identified in this study are common in the Mediterranean region. Therefore, our findings are consistent with the historical and geographical links between the Iranian population and the populations of Mediterranean region.

PAH mutation spectrum and correlation with PKU manifestation in north Jiangsu province population

“…North China (%) [6] South China (%) [15] Taiwan (%) [8] Korea (%) [15] Czech (%) [16] Lithuania (%) [16] Brazil (%) [ [9,20]. Although the exact reason behind the specific PAH mutation pattern in this area and in Northern and Western regions of China remains unclear, investigation on PAH mutation spectrum of north Jiangsu can facilitate the diagnosis and prognosis of PKU patients in this region.…”

Investigation of five common mutations on Phenylalanine Hydroxylase Gene of Phenylketonuria Patients from Two Provinces in North of Iran

“…Fifteen different mutations were observed on molecular analysis of PAH gene in 51 of the 54 alleles in Kurdish PKU patients in West of Iran. [ 8 ] The c.168 + 5G>C mutation was the most prevalent mutation with the frequency of 26%. In Kermanshah province – located at West of Iran with mainly Kurd population-p. R261Q was observed just in one chromosome of 25 PKU patients.…”

The digital epidemiology of phenylketonuria, aka folling’s disease: retrospective analysis and geographic mapping via google trends

“…35 In the southwest of Iran and the Khuzestan Province, molecular analysis confirmed detection of thirteen different mutations affecting the PAH gene which was anticipated due to the ethnic heterogeneity of the specified region. 36 In western Iran, Alibakhshi and co-workers confirmed a distinct difference existing concerning the characteristics of PAH mutations between the Kermanshah province and other areas of Iran. It has been suggested that Kermanshah, also known as the gateway to Asia, may have a unique population distribution of PAH gene mutations as it lies and 2016 versus 2017 (p<0.001).…”